Nonsense Mutations in AAGAB Cause Punctate Palmoplantar Keratoderma Type Buschke-Fischer-Brauer

Abstract

Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations-c.370C>T (p.Arg124(∗)) and c.481C>T (p.Arg161(∗))-in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity.

The Genetics of Human Skin Disease

“…2), have been identified in patients with a punctate form of palmoplantar keratoderma (Giehl et al 2012;Pohler et al 2012). The overall function of this gene is consistent with the ultrastructural findings in lesional plantar skin, which revealed vesicle defects in basal keratinocytes (Pohler et al 2012).…”

Two Japanese familial cases of punctate palmoplantar keratoderma caused by a novel AAGAB mutation, c.191_194delCAAA

“…KS occurs in both sporadic and inherited forms showing different modes of transmission, namely the X-linked form (MIM# #308700) which is caused by mutations in the KAL1 gene on Xp22.31, but also autosomal dominant forms, recessive monogenic or digenic/oligogenic conditions [2].…”

“…To our knowledge, 27 distinct AAGAB mutations were previously reported in familial and sporadic cases of PPPK1, including 11 deletion, nine nonsense, three splice site, three insertion, and one insertion-deletion mutation [1][2][3][4][5][6][7][8]. All of these were heterozygous loss-of-function mutations except for one splice-site mutation, c.451 + 1G > A, leading to an in-frame deletion that is expected to result in the loss of 30 amino acids in p34, corresponding to the entire exon 4 in AAGAB [5].…”

“…Pohler et al reported that knockdown of p34 in HaCaT cells led to increased cell division, which was linked to elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation, and they hypothesized that p34 deficiency may impair endocytic recycling of EGFR, leading to increased signaling and cellular proliferation [4]. In addition, Giehl et al demonstrated that granular staining of p34 was widely reduced in the skin of affected individuals, and they speculated that p34 plays an important role in skin integrity [2].…”

“…Although the function of p34 is not fully elucidated, it contains a Rab-like GTPase domain; therefore, it might play a pivotal role as a chaperone in clathrin-coated vesicle trafficking [1,2]. Pohler et al reported that knockdown of p34 in HaCaT cells led to increased cell division, which was linked to elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation, and they hypothesized that p34 deficiency may impair endocytic recycling of EGFR, leading to increased signaling and cellular proliferation [4].…”